Our long-term goal is to understand how nuclear receptors regulate monocyte and macrophage gene expression in the context of chronic metabolic diseases, such as atherosclerosis and obesity-induced insulin resistance. Recent studies indicate that classical activation of resident macrophages by Th1-type stimuli, such as interferon gamma, plays a key pathogenic role in both atherosclerosis and obesity-induced insulin resistance. In contrast, Th2 cytokines interleukin-4 and -13 (IL-4 and IL-13) promote alternative activation of tissue macrophages to ameliorate metabolic syndrome. Notably, we have reported that the maturation of alternatively activated macrophages in tissues is absolutely dependent on the transcriptional activity of Peroxisome Proliferator Activated Receptors gamma and delta (PPAR gamma and delta), providing a mechanistic basis for the protective functions of these receptors in obesity-induced insulin resistance and atherosclerosis. In addition to their well-established functions in macrophage biology, we recently discovered that PPAR gamma and delta are also expressed in circulating mouse monocytes, the precursors of recruited and resident tissue macrophages. Moreover, PPAR gamma and delta are transcriptionally competent in monocytic cells, suggesting that these receptors might also coordinate gene expression networks in these cells. Therefore, studies proposed in the present grant application will take molecular, cellular, and genetic approaches, including monocyte- and macrophage-specific knockouts, to further investigate how PPAR gamma and delta control the maturation of monocytes and activation of macrophages in lean and obese mice. Data from these studies will greatly enhance the molecular understanding of how PPAR gamma and delta regulate monocyte and macrophage functions under physiologic and pathophysiologic conditions, leading to better utilization of their ligands for the treatment of metabolic complications of obesity, such as atherosclerosis. The specific aims of this proposal are to: 1) Develop and validate a novel cell culture system for adoptive transfer of monocytic cells, 2) Investigate the regulatory roles of PPAR gamma and delta in monocyte biology in both mice and humans, and 3) Investigate the functions of PPARs development of advanced necrotic plaques. PUBLIC HEALTH RELEVANCE: Monocytes and macrophages are heterogeneous groups of cells that take residence in almost all organs of the body. Interestingly, activation of tissue macrophages is transcriptionally controlled by the various nuclear receptors, which can ameliorate the metabolic complications of obesity. Studies in this grant application will explore the mechanisms by which nuclear receptors control the maturation of monocytes and activation of macrophages in tissues. Insights from these studies should identify new therapeutic targets for intervening in atherosclerosis in which monocytes and macrophages play a key pathogenic role.